SLC4A11 mutations in Fuchs endothelial corneal dystrophy
SLC4A11 mutations in Fuchs endothelial corneal dystrophy
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DOI：
10.1093/hmg/ddm337
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Aung, Tin
中科院分区：
文献类型：
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作者：
Vithana, Eranga N.;Morgan, Patricio E.;Aung, Tin
原发性内皮功能障碍导致的内皮性（后）角膜营养不良包括Fuchs内皮性角膜营养不良（FECD）、后多形性角膜营养不良（PPCD）和先天性遗传性内皮营养不良（CHED）。SLC4A11基因突变最近在隐性CHED （CHED2）患者中被发现。在这项研究中，我们发现SLC4A11基因的杂合突变也会导致晚发性FECD。在89例FECD患者中发现了种族匹配对照中缺失的4个杂合突变[3个错义突变（E399K、G709E和T754M）和1个缺失突变（c.99-100delTC）]。错义突变涉及氨基酸残基，显示出高度的种间保守性，表明这些位点的突变是有害的。因此，免疫印迹分析、细胞表面定位和共聚焦免疫定位的生化实验表明，突变体编码的错义蛋白在细胞表面定位时存在缺陷。我们的数据表明，SLC4A11单倍不足和异常错误折叠蛋白的逐渐积累可能在FECD病理中起作用，SLC4A11水平的降低影响神经嵴源性角膜内皮细胞的长期生存能力。
The endothelial (posterior) corneal dystrophies, which result from primary endothelial dysfunction, include Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD) and congenital hereditary endothelial dystrophy (CHED). Mutations in SLC4A11 gene have been recently identified in patients with recessive CHED (CHED2). In this study, we show that heterozygous mutations in the SLC4A11 gene also cause late-onset FECD. Four heterozygous mutations [three missense mutations (E399K, G709E and T754M) and one deletion mutation (c.99-100delTC)] absent in ethnically matched controls were identified in a screen of 89 FECD patients. Missense mutations involved amino acid residues showing high interspecies conservation, indicating that mutations at these sites would be deleterious. Accordingly, immunoblot analysis, biochemical assay of cell surface localization and confocal immunolocalization showed that missense proteins encoded by the mutants were defective in localization to the cell surface. Our data suggests that SLC4A11 haploinsufficiency and gradual accumulation of the aberrant misfolded protein may play a role in FECD pathology and that reduced levels of SLC4A11 influence the long-term viability of the neural crest derived corneal endothelial cells.